Genomic diversity and molecular dynamics interaction on mutational variances among RB domains of SARS-CoV-2 interplay drug inactivation

Uddin, Bashir; Sajib, Emran Hossain; Hoque, Syeda Farjana; Bappy, Nazmul Islam; Elahi, Fazle; Ghosh, Arabinda; Muhit, Samuel; Hassan, Mohammad Mahmudul; Hasan, Mahmudul; Chelliah, Ramachandran; Park, Se Jin; Mony, Tamanna Jahan; Oh, Deog‐Hwan; Ahmed, Syed Sayeem Uddin

doi:10.1016/j.meegid.2021.105128

“…We then summed together expected mutations by mutation type for each gene. We considered two sources for inferred substitution rates: (1) substitution rates calculated from the 4-fold degenerate sites within SARS-CoV-2 using the global UShER phylogeny 20 , and (2) a maximum likelihood substitution matrix inferred early in the pandemic from 36 SARS-CoV-2 genomes 74 . In the main text, we present results from the first source (Fig.…”

Section: Methodsmentioning

confidence: 99%

Positive selection underlies repeated knockout of ORF8 in SARS-CoV-2 evolution

Wagner,

Kistler,

Perchetti

et al. 2024

Nat Commun

1

0

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Knockout of the ORF8 protein has repeatedly spread through the global viral population during SARS-CoV-2 evolution. Here we use both regional and global pathogen sequencing to explore the selection pressures underlying its loss. In Washington State, we identified transmission clusters with ORF8 knockout throughout SARS-CoV-2 evolution, not just on novel, high fitness viral backbones. Indeed, ORF8 is truncated more frequently and knockouts circulate for longer than for any other gene. Using a global phylogeny, we find evidence of positive selection to explain this phenomenon: nonsense mutations resulting in shortened protein products occur more frequently and are associated with faster clade growth rates than synonymous mutations in ORF8. Loss of ORF8 is also associated with reduced clinical severity, highlighting the diverse clinical impacts of SARS-CoV-2 evolution.

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“…In (A), the substitution matrix used to estimate the expected number of sites was calculated from 4-fold degenerate sites in the SARS-CoV-2 UShER phylogeny 20 . In (B), the substitution rates were inferred from all sites in the SARS-CoV-2 genome early in the pandemic 65 .…”

Section: Supplementalmentioning

confidence: 99%

“…We then summed together expected mutations by mutation type for each gene. We considered two sources for inferred substitution rates: (1) substitution rates calculated from the 4-fold degenerate sites within SARS-CoV-2 using the global UShER phylogeny 20 , and (2) a maximum likelihood substitution matrix inferred early in the pandemic from 36 SARS-CoV-2 genomes 65 . In the main text, we present results from the first source (Fig 3A ), but include results for all genes for both substitution matrices in the Supplement (S4).…”

Section: Calculating Dn/dsmentioning

confidence: 99%

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Positive selection underlies repeated knockout of ORF8 in SARS-CoV-2 evolution

Wagner,

Kistler,

Perchetti

et al. 2023

Preprint

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Knockout of the ORF8 protein has repeatedly spread through the global viral population during SARS-CoV-2 evolution. Here we use both regional and global pathogen sequencing to explore the selection pressures underlying its loss. In Washington State, we identified transmission clusters with ORF8 knockout throughout SARS-CoV-2 evolution, not just on novel, high fitness viral backbones. Indeed, ORF8 is truncated more frequently and knockouts circulate for longer than for any other gene. Using a global phylogeny, we find evidence of positive selection to explain this phenomenon: nonsense mutations resulting in shortened protein products occur more frequently and are associated with faster clade growth rates than synonymous mutations in ORF8. Loss of ORF8 is also associated with reduced clinical severity, highlighting the diverse clinical impacts of SARS-CoV-2 evolution.

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Triterpene Derivatives as Potential Inhibitors of the RBD Spike Protein from SARS-CoV-2: An In Silico Approach

Avelar

¹

,

Pedraza-González

²

,

Sinicropi

³

et al. 2023

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The appearance of a new coronavirus, SARS-CoV-2, in 2019 kicked off an international public health emergency. Although rapid progress in vaccination has reduced the number of deaths, the development of alternative treatments to overcome the disease is still necessary. It is known that the infection begins with the interaction of the spike glycoprotein (at the virus surface) and the angiotensin-converting enzyme 2 cell receptor (ACE2). Therefore, a straightforward solution for promoting virus inhibition seems to be the search for molecules capable of abolishing such attachment. In this work, we tested 18 triterpene derivatives as potential inhibitors of SARS-CoV-2 against the receptor-binding domain (RBD) of the spike protein by means of molecular docking and molecular dynamics simulations, modeling the RBD S1 subunit from the X-ray structure of the RBD-ACE2 complex (PDB ID: 6M0J). Molecular docking revealed that at least three triterpene derivatives of each type (i.e., oleanolic, moronic and ursolic) present similar interaction energies as the reference molecule, i.e., glycyrrhizic acid. Molecular dynamics suggest that two compounds from oleanolic and ursolic acid, OA5 and UA2, can induce conformational changes capable of disrupting the RBD-ACE2 interaction. Finally, physicochemical and pharmacokinetic properties simulations revealed favorable biological activity as antivirals.

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Genomic diversity and molecular dynamics interaction on mutational variances among RB domains of SARS-CoV-2 interplay drug inactivation

Cited by 3 publications

References 74 publications

Positive selection underlies repeated knockout of ORF8 in SARS-CoV-2 evolution

Positive selection underlies repeated knockout of ORF8 in SARS-CoV-2 evolution

Positive selection underlies repeated knockout of ORF8 in SARS-CoV-2 evolution

Triterpene Derivatives as Potential Inhibitors of the RBD Spike Protein from SARS-CoV-2: An In Silico Approach

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